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Vol. 61, Issue 4, 840-852, April 2002
Division of Intramural Research, National Institute of
Environmental Health Sciences, Research Triangle Park, North Carolina
(L.M.K., J.M., S.S., J.G., A.B., L.L., D.C.Z.); Department of Medicine
II, University of Mainz, Mainz, Germany (M.S.); Cardiovascular
Division, Brigham and Woman's Hospital and Harvard Medical School,
Boston, Massachusetts (J.K.L.); and Lawrence Livermore National
Laboratory, Livermore, California (H.M.)
CYP2J2 is abundant in cardiovascular tissue and active in the
metabolism of arachidonic acid to eicosanoids that possess potent anti-inflammatory, vasodilatory, and fibrinolytic properties. We cloned
and sequenced the entire CYP2J2 gene (~40.3 kb), which contains nine exons and eight introns. We then sequenced the
CYP2J2 exons and intron-exon boundaries in 72 healthy
persons representing African, Asian, and European/white
populations as part of the National Institutes of Health/National
Institute of Environmental Health Sciences Environmental Genome Single
Nucleotide Polymorphism Program. A variety of polymorphisms were
found, four of which resulted in coding changes (Arg158Cys, Ile192Asn,
Asp342Asn, and Asn404Tyr). A fifth variant (Thr143Ala) was identified
by screening a human heart cDNA library. All five variant cDNAs of
CYP2J2 were generated by site-directed mutagenesis and expressed in Sf9
insect cells by using a baculovirus system. The recombinant wild-type and variant CYP2J2 proteins immunoreacted with peptide-based antibodies to CYP2J2 and displayed typical cytochrome P450 (P450) CO-difference spectra; however, the Asn404Tyr and Ile192Asn variants also had prominent spectral peaks at 420 nm. The ability of these variants to
metabolize arachidonic acid and linoleic acid was compared with that of
wild-type CYP2J2. Three variants (Asn404Tyr, Arg158Cys, and Thr143Ala)
showed significantly reduced metabolism of both arachidonic acid and
linoleic acid. The Ile192Asn variant showed significantly reduced
activity toward arachidonic acid only. The Asp342Asn variant showed
similar metabolism to wild-type CYP2J2 for both endogenous substrates.
Based on these data, we conclude that allelic variants of the human
CYP2J2 gene exist and that some of these variants result
in a P450 protein that has reduced catalytic function. Insofar as
CYP2J2 products have effects in the cardiovascular system, we speculate
that these variants may be functionally relevant.
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